rs773045619

chr8-60865265-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_017780.4(CHD7):c.8326C>T(p.Pro2776Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,455,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.8326C>T	p.Pro2776Ser	missense_variant	38/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.8326C>T	p.Pro2776Ser	missense_variant	38/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235232 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000943

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455352 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE association Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2017

This sequence change replaces proline with serine at codon 2776 of the CHD7 protein (p.Pro2776Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs773045619, ExAC 0.002%). This variant has not been reported in the literature in individuals with CHD7-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.028	D;T
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.45		Loss of glycosylation at P2777 (P = 0.0934);.;
MVP		0.87
MPC		0.46
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773045619; hg19: chr8-61777824; COSMIC: COSV101418518; COSMIC: COSV101418518;